Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation

This cohort study investigates the association of montelukast treatment with adverse neuropsychiatric outcomes among patients with asthma or allergic rhinitis.


eMethods Data
The HCOs included in the TriNetX Network are typically large academic medical centres that provide a range of healthcare services, including emergency, outpatient, and inpatient care. A single HCO typically has more than one facility, and EHR data from all these facilities are available on the TriNetX platform. Patients are included regardless of insurance status. The quality of TriNetX data is ensured by and evaluated against pre-specified quality standards. 1 The TriNetX data has been used for epidemiological research on various neuropsychiatric outcomes. [2][3][4][5][6] TriNetX is compliant with the Health Insurance Portability and Accountability Act (HIPAA), the US federal law which protects the privacy and security of healthcare data, and any additional data privacy regulations applicable to the contributing HCO. TriNetX is certified to the ISO 27001:2013 standard and maintains an Information Security Management System (ISMS) to ensure the protection of the healthcare data it has access to and to meet the requirements of the HIPAA Security Rule. Any data displayed on the TriNetX Platform in aggregate form only contains de-identified data as per the deidentification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data is deidentified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule.
Data for this study were accessed via the TriNetX platform and analysed in June 2021 by using the TriNetX built-in query builder. All data processing was conducted using the TriNetX built-in proprietary algorithms. All diagnoses were identified using the International Classification of Diseases, tenth revision, clinical modification (ICD10-CM) codes, while dispensed prescription medicines were identified using the RxNorm codes (eTable 1).

Design
To partially control for potential unmeasured confounding by cohort and period effects in montelukast prescribing and associated factors, we divided the five-year study period, from 1 January 2015 to 31 December 2019, into five separate consecutive one-year blocks based on calendar time. Eligible patients were identified independently within each calendar year, and cohorts were defined and propensity score-matched separately for each calendar year block.

Cohort definitions
In our data, 34% of the patients with dispensed montelukast were prescribed Singulair and 66% generic form montelukast. Patients with missing information were excluded from the analyses. To control for the confounding effect of recent exposure to LTMAs, we excluded patients who had dispensed prescriptions for montelukast, zafirlukast, or zileuton six months before the index prescription. We also excluded patients who had dispensed prescriptions for zafirlukast or zileuton during the follow-up; and additionally, from the control cohorts, those who had dispensed prescriptions for montelukast.
For each given primary and secondary outcome, we included patients who did not have a recorded history of the given outcome in their EHR, ie, we modelled incident outcomes. We used a 14-day washout period after the index prescription for measuring outcomes to reduce bias from conditions already present at the time of the index prescription. The EHR data included information on whether the patient had died while in hospital but did not include information on the cause of death. Those who died as inpatients were excluded from the analyses. Due to the lack of cause of death information we were unable to establish whether these deaths could be attributable to montelukast treatment.

Propensity score-matching
We used standardized (mean) differences as a balance metric between the exposed and unexposed cohorts before and after propensity score matching. 7 Montelukast-exposed and -unexposed cohorts of asthma and allergic rhinitis patients were matched for the following covariates: age at index prescription; sex; race; type 2 diabetes mellitus; overweight and obesity; mental and behavioural disorders due to psychoactive substance use; any psychotic disorder; any mood disorder; manic episode; bipolar disorder; major depression, single episode; any anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorder; phobic anxiety; generalized anxiety; other anxiety; obsessive-compulsive disorder and behaviour (OCD); disorders of adult personality and behaviour; any sleep disorder; ischemic heart disease; vasomotor rhinitis; allergic rhinitis due to pollen; other seasonal allergic rhinitis; other allergic rhinitis; unspecified allergic rhinitis; chronic rhinitis; chronic sinusitis; reflux disease; dermatitis and eczema; cough; snoring; self-harm, including undetermined intent; history of dispensed prescriptions for: antihistamines (nasal, oral); sedating antihistamines (promethazine, diphenhydramine, hydroxyzine); non-sedating antihistamines (cetirizine, fexofenadine, loratadine); opioid analgesics; sedatives and hypnotics; antidepressants; antipsychotics; calcium channel blockers; antilipemic agents; ace inhibitors; gastric medications (including medicines used to treat reflux disease); glucocorticoids; antirheumatics; muscle relaxants; decongestants (nasal, systemic); anti-inflammatories (inhalation, nasal, topical); bronchodilators (inhalation, oral, xanthine-derivative, anticholinergic); leukotriene-modifying agents (montelukast, zafirlukast, zileuton); vilanterol; metformin; levothyroxine; antitussives and expectorants; and six most prescribed medications commonly used to treat insomnia (eszopiclone, doxepin, melatonin, temazepam, trazodone, zolpidem). These covariates were included to improve comparability of the montelukast-exposed and control (montelukast-unexposed) cohorts in relation to comorbidities and use of various other prescription medicines that could bias the comparison.
Within the asthma cohort, 76% (n=36245/47772) of montelukast-exposed patients were successfully matched with an unexposed patient. Within the allergic rhinitis cohort, 67% (n=41228/61186) of montelukast-exposed patients were successfully matched with an unexposed patient. The number of excluded patients reflects the fact that in the real-world context, the montelukast exposed and unexposed cohorts, even when these patient groups had the same underlying indication (asthma or allergic rhinitis), had differences in the distribution of potential confounding factors at baseline. This highlights the need to control for these baseline differences as potential confounders. eTable 1. Medical Codes Used in Defining Cohorts, Propensity Score Matching, and Defining Outcomes Asthma patients aged 15 ̶ 64 years at index prescription and alive for the subsequent 12 months • Montelukast-exposed patients, n=322505 • Control cohort patients, n=1344631 eFigure 1. Flow Diagram of Montelukast-Exposed and -Unexposed Asthma Groups Excluded patients exposed to LTMAs six months before index prescription or during follow-up (other than montelukast for the montelukast-exposed cohort) • Montelukast-exposed patients, n=52909 • Control cohort patients, n=299209 Excluded patients with history of COPD, OSA, or neoplasms, and patients who were pregnant or were prescribed with oral glucocorticoids at baseline or during followup.

eFigure 2. Flow Diagram of Montelukast-Exposed and -Unexposed Allergic Rhinitis Groups
Allergic rhinitis patients fulfilling all eligibility criteria before matching • Montelukast-exposed patients, n=61186 • Control cohort patients, n=138270 Excluded patients not matched at baseline (1:1 propensity score-matching) • Montelukast-exposed cohort, n=19958 • Control cohort, n=97042 Allergic rhinitis patients matched and analysed for outcomes • Montelukast-exposed patients, n=41228 • Control cohort patients, n=41228 Excluded patients exposed to LTMAs six months before index prescription or during follow-up (other than montelukast for the montelukast-exposed cohort) • Montelukast-exposed patients, n=14522 • Control cohort patients, n=36278 Excluded patients with history of COPD, OSA, neoplasms, or dyspnoea, and patients who were pregnant at baseline or during follow-up.
• Montelukast-exposed cohort, n=51865 • Control cohort, n=118489 Allergic rhinitis patients with eligible index prescription • Montelukast-exposed patients with a new montelukast prescription, n=113051 • Control cohort patients not exposed to LTMAs, n=256759